The causes that underlie primary degeneration of motoneurons in ALS remain unknown. This proposal will investigate a novel hypothesis regarding ALS pathogenesis, namely, that dysfunctional microglia are, in part, responsible for motoneuron degeneration. The rationale for this hypothesis is two-fold: on one hand experimental studies in rodents suggest that microglial activation is essential for rescuing acutely injured motoneurons and for facilitating their regeneration, and on the other hand there is now evidence that microglial cells undergo structural deterioration in the aged and, particularly, in the Alzheimer's disease brain. The latter observations suggest that progressive structural deterioration of microglia over long periods of time results in microglial malfunction and dwindling glial support to neurons, which ultimately causes neurodegeneration. We now propose to investigate whether dystrophic microglia are present in motor neuron disease (MND). The specific aims are as follows: 1) To examine post-mortem human tissue specimens from individuals who died with ALS to determine if the incidence of dystrophic microglial cells is higher than in age-matched non-ALS individuals. 2) To determine if dystrophic microglial cells are present in the recently generated transgenic ALS rat carrying the SOD1/G93A mutation. 3) To determine the effect of minocycline treatment on axotomy-induced microglial activation in wildtype Sprague Dawley rats. This last set of studies is intended to represent a proof-of-principle experiment, which will test recent claims that minocycline delays the onset of MND by inhibiting microglial activation. If this claim is true, an attenuation of axotomy-induced microglial activation with minocycline should result in delayed or impaired motoneuron regeneration after axotomy. Collectively, these studies may provide a new lead into the pathogenesis of ALS, i.e. that dystrophy and dysfunction of microglia may be involved. In addition, the minocycline experiments will help to further assess the usefulness of this drug for possible treatment of ALS.